Genome-wide approaches to transcriptional and proteomic profiling are promising tools to facilitate individualized care for patients with cancer. As such, biomarkers of therapeutic response and clinical outcome, which inform clinical decision making, will likely become cornerstones of personalized medicine in the future. Currently, the application of such technologies to research provides insights into the biologic basis to cancer development, progression, and response to therapy that were previously not possible.
Recently, using genome-wide expression analysis and a series of functional assays, the BCL-2 antagonist of cell death (BAD) apoptosis pathway and the phosphorylation status of the BAD protein was identified to be associated with the development of ovarian cancer resistance to platinum-based therapy, in vitro and in vivo. (Marchion, et al. BAD phosphorylation determines ovarian cancer chemo-sensitivity and patient survival. Clin Cancer Res. 2011 Oct. 1; 17(19):6356-66). Furthermore, the expression of the BAD pathway is associated with overall survival for patients with ovarian cancer. BCL-2 family proteins are key regulators of apoptosis. Pro-apoptotic BAX and BAK drive cell death by increasing mitochondrial outer membrane permeability, resulting in cytochrome c release, cytoplasmic caspase activation, and, ultimately, cell death. Anti-apoptotic proteins such as BCL-2, BCL-xL, and BCL-W promote survival by binding and inhibiting BAX and BAK. A third group of BCL-2 family members, which includes BAD, BID, BIM, NOXA, and PUMA, promote apoptosis by directly binding and inhibiting the anti-apoptotic BCL-2 proteins. (Youle and Strasser, The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9: 47-59; Danial, BAD: undertaker by night, candyman by day. Oncogene 2008; 27 Suppl 1: S53-70) It is believed the phosphorylation status of BAD influences its ability to bind BCL and BCL-xL, levels of unbound of BAX, and hence mitochondrial membrane permeability and apoptosis.
What is needed is a method of diagnosing, treating, determining survival, and monitoring progression of cancers using BAD pathway proteins.